Download Genetic Testing for Susceptibility to Breast and Ovarian Cancer (e.g.

Cigna Medical Coverage Policy
Subject
Genetic Testing for
Susceptibility to Breast and
Ovarian Cancer (e.g., BRCA1 &
BRCA2)
Table of Contents
Coverage Policy .................................................. 1
General Background ........................................... 8
Coding/Billing Information ................................. 19
References ........................................................ 19
Effective Date ............................ 8/15/2014
Next Review Date ...................... 8/15/2015
Coverage Policy Number ................. 0001
Hyperlink to Related Coverage Policies
Genetic Counseling
Genetic Testing of Heritable Disorders
Prophylactic Mastectomy
Prophylactic Oophorectomy or Salpingooophorectomy With or Without
Hysterectomy
Transvaginal Ultrasound, Non-Obstetrical
INSTRUCTIONS FOR USE
The following Coverage Policy applies to health benefit plans administered by Cigna companies. Coverage Policies are intended to provide
guidance in interpreting certain standard Cigna benefit plans. Please note, the terms of a customer’s particular benefit plan document
[Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may
differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan
document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit
plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage
mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific
instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable
laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular
situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for
treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support
medical necessity and other coverage determinations. Proprietary information of Cigna. Copyright ©2014 Cigna
Coverage Policy
Coverage of genetic testing for susceptibility to breast and ovarian cancer subject to the terms,
conditions and limitations as described in the applicable benefit plan’s schedule of copayments. Please
refer to the applicable benefit plan document and schedules to determine benefit availability and the
terms, conditions and limitations of coverage.
1. Known Familial Mutation
Cigna covers BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer in adults
as medically necessary with single site analysis for the known familial variant (Current Procedural
®
Terminology [CPT] codes 81215, 81217) for a biologically-related individual from a family with a known
BRCA1 or BRCA2 mutation when a recommendation for testing is confirmed by ONE of the following:
•
•
•
an independent Board-Certified or Board-Eligible Medical Geneticist
an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic
Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not
excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself).
a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in
Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American
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Coverage Policy Number: 0001
Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory
(Genetic nurses are not excluded if they are employed by or contracted with a laboratory that is part of
an Integrated Health System which routinely delivers health care services beyond just the laboratory
test itself).
who:
•
•
•
has evaluated the individual
completed a three generation pedigree
intends to engage in post-test follow-up counseling
2. Personal History of Breast Cancer
Cigna covers BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer in adults
with full sequence analysis and duplication/deletion analysis of common variants (CPT codes 81211,
81214, 81216) as medically necessary when there is a personal history of breast cancer and a
recommendation for testing is confirmed by ONE of the following:
•
•
•
an independent Board-Certified or Board-Eligible Medical Geneticist
an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic
Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not
excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself).
a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in
Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American
Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory
(Genetic nurses are not excluded if they are employed by or contracted with a laboratory that is part of
an Integrated Health System which routinely delivers health care services beyond just the laboratory
test itself).
who:
•
•
•
has evaluated the individual
completed a three generation pedigree
intends to engage in post-test follow-up counseling
for ANY of the following indications:
•
•
•
•
•
•
•
•
•
•
diagnosed at age 45 or younger
diagnosed at age 50 or younger with at least one close blood relative* with breast cancer at any age
diagnosed with two breast primaries (includes bilateral disease or cases where there are two or more
clearly separate ipsilateral primary tumors) when the first breast cancer diagnosis occurred prior to age
50
diagnosed at age 60 or younger with a triple negative breast cancer
diagnosed at age 50 or younger with a limited family history (e.g., fewer than two first- or second degree
female relatives or female relatives surviving beyond 45 years in the relevant maternal and/or paternal
lineage)
diagnosed at any age and there are at least two close blood relatives* with breast cancer at any age
diagnosed at any age with at least one close blood relative* with breast cancer at age 50 or younger
diagnosed at any age and there are at least two close blood relatives* with pancreatic cancer or
prostate cancer (Gleason score ≥7) at any age
diagnosed at any age with at least one close blood relative* with epithelial ovarian cancer, fallopian
tube, or primary peritoneal cancer
close male blood relative* with breast cancer
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Coverage Policy Number: 0001
•
individual of Ashkenazi Jewish descent (testing in this situation is only covered for the three founder
mutations [CPT code 81212] and not for full sequence analysis and duplication/deletion analysis of
common variants)
3. Personal History of Cancer
Cigna covers BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer in adults
with full sequence analysis and duplication/deletion analysis of common variants (CPT codes 81211,
81214, 81216) as medically necessary in an adult when a recommendation for testing is confirmed by
ONE of the following:
•
•
•
an independent Board-Certified or Board-Eligible Medical Geneticist
an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic
Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not
excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself).
a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in
Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American
Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory
(Genetic nurses are not excluded if they are employed by or contracted with a laboratory that is part of
an Integrated Health System which routinely delivers health care services beyond just the laboratory
test itself).
who:
•
•
•
has evaluated the individual
completed a three generation pedigree
intends to engage in post-test follow-up counseling
for any of the following indications:
•
•
•
•
personal history of epithelial ovarian, fallopian tube, or primary peritoneal cancer
personal history of male breast cancer
personal history of pancreatic cancer or prostate cancer (Gleason score ≥7) at any age with two or
more close blood relatives* with breast, ovarian, pancreatic cancer, or prostate cancer (e.g., Gleason
score ≥7) at any age
personal history of pancreatic cancer at any age with Ashkenazi Jewish ancestry and one or more close
blood relatives* with breast, ovarian, pancreatic cancer, or prostate cancer (Gleason score ≥7) at any
age (testing in this situation is only covered for the three founder mutations [CPT code 81212] and not
for full sequence analysis and duplication/deletion analysis of common variants)
4. Family History of Breast, Ovarian or Pancreatic Cancer
Cigna covers BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer in adults
with full sequence analysis and duplication/deletion analysis of common variants** (CPT codes 81211,
81214, 81216) as medically necessary when there is no personal history of breast or ovarian cancer and
a recommendation for testing is confirmed by ONE of the following:
•
•
•
an independent Board-Certified or Board-Eligible Medical Geneticist
an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic
Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not
excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself).
a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in
Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American
Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory
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Coverage Policy Number: 0001
(Genetic nurses are not excluded if they are employed by or contracted with a laboratory that is part of
an Integrated Health System which routinely delivers health care services beyond just the laboratory
test itself).
who:
•
•
•
has evaluated the individual
completed a three generation pedigree
intends to engage in post-test follow-up counseling
for a family history of ANY of the following:
•
•
•
•
•
•
first- or second-degree blood relative with a history of breast cancer and any of the following:
 diagnosed at age 45 or younger
 diagnosed at age 50 or younger with at least one additional close blood relative* with breast
cancer at any age
 diagnosed with two breast primaries (includes bilateral disease or cases where there are two
or more clearly separate ipsilateral primary tumors) when the first breast cancer diagnosis
occurred prior to age 50
 diagnosed at age 60 or younger with a triple negative breast cancer
 diagnosed at age 50 or younger with a limited family history (e.g., fewer than two first- or
second degree female relatives or female relatives surviving beyond 45 years in the relevant
maternal and/or paternal lineage)
 diagnosed at any age and there are at least two close blood relatives* with breast cancer at
any age
 diagnosed at any age with at least one close blood relative* with breast cancer at age 50 or
younger
 diagnosed at any age and there are at least two close blood relatives* with pancreatic cancer
or prostate cancer (e.g., Gleason score ≥7) at any age
 diagnosed at any age with at least one close blood relative* with epithelial ovarian cancer,
fallopian tube, or primary peritoneal cancer
 close male blood relative* with breast cancer
 individual of Ashkenazi Jewish descent (testing in this situation is only covered for the three
founder mutations (CPT code 81212) and not for full sequence analysis and
duplication/deletion analysis of common variants)
first- or second-degree blood relative with a history of epithelial ovarian, fallopian tube, or primary
peritoneal cancer
first- or second-degree blood relative with a history of male breast cancer
first- or second-degree relative with a history of pancreatic cancer or prostate cancer (Gleason score ≥7)
at any age with two or more close blood relatives* with breast, ovarian, pancreatic cancer, or prostate
cancer (Gleason score ≥7) at any age
personal history of pancreatic cancer at any age with Ashkenazi Jewish descent and one or more close
blood relatives* with breast, ovarian, pancreatic cancer, or prostate cancer (Gleason score ≥7) at any
age (testing in this situation is only covered for the three founder mutations [CPT code 81212] and not
for full sequence analysis and duplication/deletion analysis of common variants)
third-degree blood relative with breast and/or epithelial ovarian/fallopian tube/primary peritoneal cancer
with two or more close blood relatives* with breast and/or ovarian cancer (with at least one close blood
relative with breast cancer prior to age 50)
** Testing of unaffected individuals should only be considered when an appropriate family member is
unavailable for testing. Significant limitations of interpreting test results for an unaffected individual should be
discussed.
5. Validated Risk Assessment Tool
Cigna covers BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer in an
adult with full sequence analysis and duplication/deletion analysis of common variants (CPT codes
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Coverage Policy Number: 0001
81211, 81214, 81216) as medically necessary when a recommendation for testing is confirmed by ONE
of the following:
•
•
•
an independent Board-Certified or Board-Eligible Medical Geneticist
an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic
Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not
excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself).
a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in
Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American
Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory
(Genetic nurses are not excluded if they are employed by or contracted with a laboratory that is part of
an Integrated Health System which routinely delivers health care services beyond just the laboratory
test itself).
who:
•
•
•
has evaluated the individual
completed a three generation pedigree
intends to engage in post-test follow-up counseling
and the individual has at least a 10% probability of carrying a BRCA1 or BRCA2 mutation as determined
using a validated risk assessment tool (e.g., BRCAPRO, University of Pennsylvania [UPenn I or UPENN
II], BOADICEA, or Tyrer-Cusick).
*A close blood relative/close family member includes first-, second-, and third-degree relatives on the same side
of family.
A first-degree relative is defined as a blood relative with whom an individual shares approximately 50% of
his/her genes, including the individual's parents, full siblings, and children.
A second-degree relative is defined as a blood relative with whom an individual shares approximately 25% of
his/her genes, including the individual's grandparents, grandchildren, aunts, uncles, nephews, nieces and halfsiblings.
A third-degree relative is defined as a blood relative with whom an individual shares approximately 12.5% of
his/her genes, including the individual’s great-grandparents and first-cousins.
6. Uncommon Large Rearrangement/Duplication and Deletion Testing
Cigna covers testing for uncommon large rearrangements/uncommon duplication and deletion variants
®
(e.g., BRACAnalysis Rearrangement Test [BART]) (CPT code 81213) as medically necessary when
BOTH of the following criteria are met:
•
•
criteria for BRCA1 and BRCA2 genetic testing as noted above are met including an evaluation and
recommendation for testing confirmed by ONE of the following:
 an independent Board-Certified or Board-Eligible Medical Geneticist
 an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic
Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not
excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself).
 a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice
Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the
American Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic
testing laboratory (Genetic nurses are not excluded if they are employed by or contracted with a
laboratory that is part of an Integrated Health System which routinely delivers health care services
beyond just the laboratory test itself).
conventional BRCA1/BRCA2 testing (e.g., sequence analysis and testing for the five common large
rearrangements) is negative
Page 5 of 23
Coverage Policy Number: 0001
7. Multi-Gene Panels
Cigna covers BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian cancer with
multi-gene next-generation sequencing panels as medically necessary when a recommendation for
testing is confirmed by ONE of the following:
•
•
•
an independent Board-Certified or Board-Eligible Medical Geneticist
an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic
Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not
excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health
System which routinely delivers health care services beyond just the laboratory test itself).
a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in
Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American
Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory
(Genetic nurses are not excluded if they are employed by or contracted with a laboratory that is part of
an Integrated Health System which routinely delivers health care services beyond just the laboratory
test itself).
who:
•
•
•
has evaluated the individual
completed a three generation pedigree
intends to engage in post-test follow-up counseling
and ALL of the following criteria are met:
•
•
•
all genes in the panel are relevant to the personal and family history for the individual being tested
criteria for genetic testing for BRCA1 and BRCA2 genetic testing for susceptibility to breast or ovarian
cancer as noted above are met
individual meets criteria for ONE of the following hereditary cancer syndromes:

Li-Fraumeni syndrome (LFS) with ANY of the following:
o Classic LFS criteria with ALL of the following:
 diagnosed age <45 years with a sarcoma
 a first degree relative diagnosed age <45 years with cancer
 an additional first or second degree relative* in the same lineage with cancer
diagnosed age <45 years, or a sarcoma at any age
o Chompret LFS criteria with ANY of the following:
 a tumor from LFS tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma,
brain tumor, breast cancer, adrenocortical carcinoma, leukemia, lung
bronchoalveolar cancer) before 46 years of age and one first- or seconddegree* relative with any of the aforementioned cancers (other than breast
cancer if the proband has breast cancer) before the age of 56 years or with
multiple primaries at any age
 multiple tumors (except multiple breast tumors), two of which belong to LFS
tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, breast
cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) with
the initial cancer occurring before the age of 46 years
 adrenocortical carcinoma or choroid plexus carcinoma at any age of onset,
regardless of the family history
o with breast cancer ≤ 35 years with a negative BRCA1/BRCA2 test and negative TP53
test (BRCA1/BRCA2 performed first, and if negative followed by TP53)

Cowden Syndrome (CS)/PTEN Hamartoma Tumor Syndrome (PHTS) with ANY of the
following:
o meets clinical diagnostic criteria for CS
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Coverage Policy Number: 0001
o
o
a personal history of ONE if the following:
 Bannayan-Riley-Ruvalcaba syndrome (BRRS)
 Adult Lhermitte-Duclos disease (cerebellar tumors)
 Autism spectrum disorder and macrocephaly
 two or more biopsy-proven trichilemmomas
 two or more major criteria** with one being macrocephaly
 three major criteria** without macrocephaly
 one major and three minor criteria**
 ≥ four minor criteria**
at-risk individual with a first-degree relative* with a clinical diagnosis of CS or BRRS for
whom testing has not been performed and the relative has EITHER of the following:
 one major criterion**
 two minor criteria**
**Major criteria:
Breast cancer
Endometrial cancer
Follicular thyroid cancer
Multiple gastrointestinal (GI) hamartomas or ganglioneuromas
Macrocephaly (megalocephaly) (i.e., ≥97%, 58 cm in adult women, 60 cm in adult men)
Macular pigmentation of glans penis
Mucocutaneous lesions (e.g., one biopsy proven trichilemmoma, multiple palmoplantar keratosis,
multifocal or extensive oral mucosal papillomatosis, multiple cutaneous facial papules)
Minor criteria:
Autism spectrum disorder
Colon cancer
Esophageal glycogenic acanthosis (≥3)
Lipomas
Intellectual disability (i.e., IQ ≤75)
Papillary or follicular variant of papillary thyroid cancer
Thyroid structural lesions (e.g., adenoma, nodule[s], goiter)
Renal cell carcinoma
Single GI hamartoma or ganglioneuroma
Testicular lipomatosis
Vascular anomalies (including multiple intracranial developmental venous anomalies)
Non-Coverage
Cigna does not cover BRCA1/BRCA2 genetic testing for susceptibility to breast or ovarian cancer for
any other indication including any of the following because it is considered not medically necessary for
these indications:
•
•
•
genetic screening in the general population
testing of individuals with no personal history of breast or ovarian cancer, except as noted above
testing of individuals under 18 years of age
Cigna does not cover the following genetic testing for susceptibility to breast and ovarian cancer
because each is considered experimental, investigational or unproven (this list may not be all
inclusive):
•
•
other genetic tests for susceptibility to breast and ovarian cancer (e.g., candidate breast cancer
susceptibility genes and single nucleotide polymorphisms [SNPs] testing)
genetic testing with multi-gene next-generation sequencing panels for any other indication than noted in
criteria above
Page 7 of 23
Coverage Policy Number: 0001
General Background
Among women, breast cancer is the most commonly diagnosed cancer after non-melanoma skin cancer and is
the second leading cause of cancer death after lung cancer. Ovarian cancer is the ninth most common cancer
and is noted to be the fifth most deadly (National Cancer Institute [NCI], 2014a). Epithelial ovarian cancer, which
is cancer that begins in the cells on the surface of the ovary, comprises the majority of malignant ovarian
neoplasm. Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States
®
and its fifth most common cause of cancer mortality in women (National Comprehensive Cancer Network
®
[NCCN ], 2014c).
While the vast majority of breast cancer cases do not demonstrate strong familial tendencies, it has been
reported that 5–10% are due to inherited forms of the disease, with similar rates reported for ovarian cancer
(NCI, 2014a). Several genes associated with the predisposition to breast and ovarian cancers have been
identified. Specific genetic mutations found in two autosomal dominant cancer predisposition genes, BRCA1
(BReast CAncer Susceptibility 1) and BRCA2 (BReast CAncer Susceptibility 2), are thought to account for the
majority of inherited forms of breast and ovarian cancers. The autosomal dominant inheritance of breast/ovarian
cancer is characterized by transmission of the cancer predisposition through either the mother’s or father’s side
of the family. When the parent carries an autosomal dominant genetic predisposition, the child has a 50%
chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone
with this predisposition will develop cancer. The risk of developing cancer depends on numerous variables,
including the penetrance of the mutation, the gender of the individual and the age of the individual. It is also
noted that both males and females can inherit and transmit an autosomal dominant cancer predisposition. The
family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following
(NCI, 2013a):
• multiple cancers within a family
• cancers typically occur at an earlier age than in sporadic cases (i.e., cancers not associated with genetic
risk)
• two or more primary cancers in a single individual. This could be multiple primary cancers of the same
type (e.g., bilateral breast cancer) or primary cancers of different types (e.g., breast and ovarian)
• cases of male breast cancer
As the result of cultural and historical factors (e.g., population isolation), certain mutations have been found at
higher frequencies in the founder populations of certain ethnic groups. A founder population is created when a
small number of individuals from a larger population, carrying only a small fraction of the genetic variation of the
original population, establish a new population through their descendents. As a result, the new population may
be distinctively different genetically from the original larger population. Three characteristically recurrent BRCA1
and BRCA2 mutations have been identified in Ashkenazi Jewish individuals (i.e., a genetically distinct
population of Jewish people of eastern and central European ancestry).
The goal of BRCA1 and BRCA2 testing is to provide patients and their physicians with information that will allow
them to make informed decisions regarding cancer prevention, screening, surveillance, and treatment options
(e.g., prophylactic surgery). A significant benefit of genetic testing is the ability to quantify cancer risk estimates
more precisely, thereby improving the process of determining the most appropriate management strategies in
patients who test positive. For patients who test negative, unnecessary treatment (e.g., prophylactic surgery)
may be avoided.
There are some histopathologic features that have been noted to occur more frequently in breast cancers that
are associated with BRCA1 or BRCA2 mutation. Several studies have demonstrated that BRAC1 breast cancer
is more likely to be characterized as estrogen receptor (ER) negative, progesterone receptor (PR) negative, and
human epidermal growth factor receptor 2 (HER2) negative, also referred to as triple negative breast cancer
(NCCN, 2014b; NCI, 2014a). Studies have indicated BRCA1 mutations in 9% to 28% of patients with triplenegative breast cancer (NCCN, 2014b).
There is evidence in the published, peer-reviewed scientific literature to demonstrate that testing methods used
to identify BRCA mutations are accurate in detecting specific mutations. If a BRCA1 or BRCA2 mutation is
identified within a family, unaffected family members can also be tested for the presence of a mutation, and
those testing negative can be provided with the reassurance that their risk of developing breast or ovarian
Page 8 of 23
Coverage Policy Number: 0001
cancer is more similar to that of the general population. Sensitivity of BRCA testing has been reported to be up
to 98% of all mutations, and sequencing should detect almost 100% of all nucleotide differences. The specificity
of BRCA testing has not been well studied.
Evidence in the published, peer-reviewed scientific literature indicates that BRCA1 and BRCA2 genetic testing is
appropriate for a specific subset of adult individuals who have been identified to be at high risk for hereditary
breast and ovarian cancers. Furthermore, several specialty organizations, including the NCCN, American
College of Medical Genetics (ACMG), and American Society of Clinical Oncology (ASCO), have issued
statements recognizing the role of BRCA testing in the management of at-risk patients. The U.S. Preventive
Services Task Force (USPSTF) has published recommendations regarding genetic risk assessment and BRCA
mutation testing for breast and ovarian cancer susceptibility. Studies have demonstrated that patients with
BRCA mutations are at increased risk for developing breast and ovarian cancer.
In addition to the criteria established by several professional organizations, there are several models that have
been developed and are available to estimate the probability of an individual carrying a cancer-predisposing
BRCA1 and BRCA2 mutation. The models include those using logistic regression, genetic models using
Bayesian analysis and empiric observations. The use of prediction models has been shown to increase the
power to discriminate which patients are most likely to be identified as BRCA1 or BRCA2 mutation carriers. The
power of several of the models has been compared in different studies and currently there is no one model that
is consistently superior to others (NCI, 2013a). The performance of the models can vary in specific ethnic
groups. Also it has been shown that the risk models are sensitive to the amount of family history available and
do not perform as well with limited family information. Validated risk assessment tools include: Berry-AquilarParmigiani (BRCAPRO), Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm
(BOADICEA), Tyrer-Cuzick—also known as International Breast Cancer Intervention Study [IBIS}, and
University of Pennsylvania [UPenn I or UPENN II]).
There is insufficient evidence in the published, peer-reviewed scientific literature to support the use of genetic
testing for susceptibility to breast and ovarian cancer for the following:
• testing in the general population
• testing of unaffected individuals, in the absence of a known mutation or family history
• patients under 18 years of age, as this population has not been well-studied
Testing Strategy
Genetic testing should be undertaken only after independent genetic counseling has been provided to patients
in order to assist in complex clinical decision-making. Post-genetic testing counseling should be planned. The
genetic counseling should be provided by an independent specialty-trained professional such as a medical
geneticist or a genetic counselor who is an American Board of Medical Genetics or American Board of Genetic
Counseling certified genetic counseling professional who is unaffiliated with the genetic testing lab performing
the test(s).The NCCN guidelines note that genetic counseling is a critical component of the cancer risk
assessment process. Pre-test counseling should include a discussion of why the test is being offered and how
test results may impact medical management, cancer risks associated with the gene mutation in question, the
significance of possible test results, the likelihood of a positive result, technical aspects and accuracy of the test,
and economic considerations (NCCN, 2014b). Post-test counseling includes disclosure of results, discussion of
the significance of the results, an assessment of the impact of the results on the emotional state, a discussion of
the impact of the results on the medical management of the individual, and how and where the patient will be
followed (NCCN, 2014b).
™
According to the NCCN Guidelines for the majority of families with an unknown mutation status, it is best to
consider testing an affected family member first, especially a family member with disease, bilateral diseases, or
multiple primaries, since that individual is most likely to test positive (NCCN, 2014b). In cases where there are
no affected individuals available or willing to undergo testing, then research and individualized
recommendations for management are based on the personal and family history. In general, the first person to
be tested in a family would undergo complete sequence analysis of both the BRCA1 and BRCA2 genes. If a
mutation is identified, relatives may be tested only for that specific mutation. For patients of Ashkenazi Jewish
descent, initial testing will generally be done only for the three specific mutations that account for most
hereditary breast and ovarian cancer in that population. The most common variants found in these women are
185delAG and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene. If the test results are negative,
Page 9 of 23
Coverage Policy Number: 0001
full analysis of the BRCA1 and BRCA2 genes may or may not be done, according to the patient's personal and
family history.
®
BRACAnalysis Rearrangement Test (BART) (Myriad Genetic Laboratories, Inc., Salt Lake City, UT) was
introduced in 2006 for use on patient samples that meet defined clinical criteria. This test is utilized to detect
rare, large rearrangements of DNA in the BRCA1 and BRCA2 genes. It is intended for use only in individuals at
an exceptionally high risk for breast cancer who have previously tested negative for sequence mutations and
common large rearrangements on Myriad Genetics standard BRACAnalysis test. All coding exons of
BRCA1/BRCA2 and their respective promoters are examined for evidence of deletions and duplications by
quantitative endpoint PCR analysis. Genomic DNA is analyzed by either multiplex quantitative PCR or
microarray-CGH analysis to determine copy number abnormalities indicative of deletion or duplication mutations
across the BRCA1 or BRCA2 genes.
®
BRACAnalysis (Myriad Genetics, Inc., Salt Lake City, UT) is a genetic test for BRCA1 and BRCA2 mutations.
According to the Myriad website the test includes:
®
• Single Site BRACAnalysis : This test includes the DNA sequence analysis for a specified variant in
BRCA1 and/or BRCA2, also known as mutation specific. It is a test for a specified mutation in BRCA1
and BRCA2. This is used when there are known familial mutations.
®
• Multisite 3 BRACAnalysis : this test is a DNA sequence analysis for specified sequence portions of
BRCA1 and BRCA 2. This testing is for individuals of Ashkenazi ancestry. It tests for the three most
common abnormalities found in people of this heritage.
• Integrated BRACAnalysis includes BART as part of BRCA1 and BRCA2 gene analysis. The test
examines the full gene sequence of BRCA1 and BRCA2 genes, along with the detection of five specific
large genomic rearrangements of BRCA1 gene. These are thought to account for nearly half of all such
rearrangements. A rearrangement is a structural alteration in a chromosome that usually involves
breakage and reattachment of a segment of chromosome material, resulting in an abnormal
configuration (Petrucelli, et al., 2007). Myriad will perform reflex testing- testing for uncommon large
rearrangements when sequence analysis testing is negative.
Rearrangements, such as large genomic alterations including translocations, inversions, or large deletions or
insertions are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less common
in BRCA2 and in individuals of Ashkenazi Jewish descent (NCI, 2013a; Unger, et al., 2000; Walsh, et al., 2006;
Palma, et al., 2008). The NCCN guidelines note that comprehensive genetic testing includes full sequencing of
BRCA1/BRCA2 and the detection of large genomic rearrangements. The NCCN guidelines notes that certain
large genomic rearrangements are not detectable by a primary sequencing assay, therefore additional testing
may be needed in some cases (NCCN, 2014b).
Literature Review for BRACAnalysis Rearrangement Test (BART): Judkins et al. (2012) reported on the
prevalence of large rearrangements in BRCA1/BRCA2 genes in 48,456 patients with diverse clinical histories
and ancestries that were referred for clinical molecular testing for suspicion of hereditary breast and ovarian
cancer. Data were analyzed for two groups of patients. The ‘‘high-risk’’ group consisted of 25,535 individuals for
whom the test ordered was Comprehensive BRACAnalysis, and who met clinical criteria predicting a relatively
high probability of carrying a mutation in BRCA1 or BRCA2. The ‘‘elective’’ group included 22,921 individuals
not meeting the high-risk criteria, but for whom BART was ordered as an elective test to be run only if no
deleterious mutation was detected by BRCA1/2 sequencing and a 5-site Large Rearrangement Panel (LRP).
Eighty-one different large rearrangements (LRs) were detected in BRCA1 and 27 LRs in BRCA2 in the group of
48,456 patients. The study found BRCA1/2 mutation prevalence among the high-risk patients was 23.8%
compared with 8.2% for the elective group. The mutation profile for high-risk patients was 90.1% sequencing
mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. It was theorized that
this difference may reflect the bias in high-risk patients to carry mutations in BRCA1, which has a higher
penetrance and frequency of LRs compared with BRCA2. Significant differences in the prevalence and types of
LRs were found in patients of different ancestries. LR mutations were noted to be significantly more common in
Latin American/Caribbean patients.
Palma et al. (2008) conducted a study to define the prevalence and spectrum of point mutations and genomic
rearrangements in BRCA genes in a large U.S. high-risk clinic population of both non-Ashkenazi and Ashkenazi
Jewish descent, using a sample set representative of the U.S. genetic testing population. The study included
251 probands with commercial testing for BRCA1 and BRCA2, with an estimated prevalence of BRCA mutation
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≥10% using the Myriad II model and a DNA sample available. Individuals without deleterious point mutations
were screened for genomic rearrangements in BRCA1 and BRCA2. The study found that in the 136 nonAshkenazi Jewish probands, 36 (26%) BRCA point mutations and 8 (6%) genomic rearrangements (7 in BRCA1
and 1 in BRCA2) were identified. Forty-seven of the 115 (40%) Ashkenazi Jewish probands no genomic
rearrangements were identified in the group without mutations. In the non-Ashkenazi Jewish probands, genomic
rearrangements constituted 18% of all identified BRCA mutations.
Walsh et al. (2006) studied the frequency and type of undetected cancer-predisposing mutations in BRCA 1,
BRCA2 and other genes associated with breast cancer (CHEK2, TP53, and PTEN) among patients with breast
cancer from high-risk families with negative (wild-type) genetic test results for BRCA1 and BRCA2. The study
included probands from 300 families with 4 or more cases of breast or ovarian cancer but with negative (wildtype) commercial genetic test results for BRCA1 and BRCA2. The study found that of the 300 probands, 52
(17%) carried previously undetected mutations, including 35 (12%) with genomic rearrangements of BRCA1 or
BRCA2. With the BRCA1 and BRCA2, 22 different genomic rearrangements were found, of sizes less than 1 kb
to greater than 170 kb—of these, 14 were not previously described and all were individually rare.
Unger et al. (2000) examined the frequency of genomic rearrangements in BRCA1 in 42 families with breast and
ovarian cancer who were seeking genetic testing and were subsequently found to be negative for BRCA1 and
BRCA2 coding-region mutations. The exon 13 duplication was detected in one family, and four families were
found to have other genomic rearrangements. Four of five families with BRCA1 genomic rearrangements
included at least one individual with both breast and ovarian cancer— four (30.8%) of 13 families with a case of
multiple primary breast and ovarian cancer had a genomic rearrangement in BRCA1. The families found to have
genomic rearrangements had prior probabilities of having a BRCA1 mutation that ranged from 33% to 97%
(mean 70%). The families without rearrangements the prior probabilities of having a BRCA1 mutation ranged
from 7% to 92% (mean 37%).
Testing Results
A positive test reveals the presence of a mutation in either the BRCA1 or BRCA2 gene that prevents the
translation of the full-sized protein or that is known to interfere with protein function in other ways. A true positive
result is the patient who is a carrier of an alteration in the known cancer-predisposing gene. A woman who
carries a mutation with such a deleterious effect has a lifetime breast cancer risk of 60–85% and a significantly
increased risk of ovarian cancer.
A negative test result is interpreted within the context of a patient's individual and family cancer history, notably
regarding whether a family member has previously been identified as possessing a mutation. The affected
individual may still have an inherited predisposing mutation in one of the BRCA genes or in another gene that
predisposes to breast or ovarian cancer. An individual identified as at-risk who does not carry a BRCA1 or
BRCA2 mutation that has been positively identified in another family member is considered to have a true
negative result.
A person is considered to have an indeterminate result if that person is not a carrier of a known cancerpredisposing gene and the carrier status of other family members is either also negative or unknown (NCCN,
2014b). In some situations, especially where a single base pair change or missense mutation is identified,
interpretation of results is more difficult. Single base pair changes do not always result in a nonfunctional gene
product. Missense mutations are typically reported as indeterminate results.
Results are considered inconclusive if the individual is a carrier of an alteration in a gene that currently has no
known significance.
Multi-Gene Panel Testing for Susceptibility of Breast and Ovarian Cancer
Multi-gene panels for hereditary ovarian and breast cancer (HBOC) syndromes are available. In general the
panel will test simultaneously for several genes and conditions associated with HBOC. The genes included and
the methods used in multi-gene panels vary by laboratory. Testing with a panel may be indicated when the
individual has symptomatology or family history that is suggestive of more than one syndrome associated with
HBOC. The genes included in the test should be relevant to the personal and family history for the individual
being tested.
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In addition to testing for BRCA1/BRCA2, hereditary breast and ovarian cancer syndromes include (NCCN
2014b; NCI 2014a; Eng, 2014; Schneider, et al., 2013):
Li-Fraumeni syndrome (LFS): LFS is a rare hereditary cancer syndrome associated with germline TP53 gene
mutations. It is estimated to be involved in approximately 1% of hereditary breast cancer cases. LFS is a cancer
predisposition syndrome associated with the development of the tumors including: soft tissue sarcoma,
osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias.
LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for
multiple primary cancers. Inheritance is autosomal dominant, and the condition is highly penetrant with the risks
for cancer in LFS estimated to be 50% by age 30 years and 90% by age 60 years with a penetrance of at least
50% by age 50 years.
•
LFS testing criteria includes ANY of the following (NCCN, 2014b):
 Individual from a family with a known TP53 mutation
 Classic LFS criteria includes a combination of the ALL of the following:
o an individual diagnosed age <45 years with a sarcoma
o a first degree relative diagnosed age <45 years with cancer
o an additional first or second degree relative in the same lineage with cancer diagnosed
age <45 years, or a sarcoma at any age
 Chompret criteria includes ANY of the following:
o Individual with a tumor from LFS tumor spectrum (e.g., soft tissue sarcoma,
osteosarcoma, brain tumor, breast cancer, adrenocortical carcinoma, leukemia, lung
bronchoalveolar cancer) before 46 years of age, and at least one first- or seconddegree relative with any of the aforementioned cancers (other than breast cancer if the
proband has breast cancer) before the age of 56 years or with multiple primaries at any
age
o Individual with multiple tumors (except multiple breast tumors), two of which belong to
LFS spectrum with the intimal cancer occurring before the age of 46 years
o Individual with adrenocortical carcinoma or choroid plexus carcinoma at any age of
onset, regardless of the family history
 Early onset breast cancer: Individual with breast cancer ≤ 35 years with a negative
BRCA1/BRCA2 test
Cowden syndrome (CS): CS is a rare hereditary cancer syndrome. The incidence is of CS is reported to
be one in 200,000. It is an autosomal dominant condition associated with germline mutation in the PTEN
gene. CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the
thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and
papillomatous papules, which present by the late 20s.
•
CS testing criteria for this condition includes ANY of the following (NCCN, 2014b):
 Individual from a family with a known PTEN mutation
 Individual meeting clinical diagnostic criteria for CS
 Individual with a personal history of ONE if the following:
o Bannayan-Riley-Ruvalcaba syndrome (BRRS) or
o Adult Lhermitte-Duclos disease (cerebellar tumors)
o Autism spectrum disorder and macrocephaly
o Two or more biopsy-proven trichilemmomas
o Two or more major criteria (one must be macrocephaly)*
o Three major criteria, without macrocephaly*
o One major and three minor criteria*
o ≥ four minor criteria*
• At-risk individual with a relative with a clinical diagnosis of CS or BRRS for whom testing has not been
performed. The at-risk relative must have ONE of the following:
 Any one major criterion*
 Two minor criteria*
*Major criteria:
Breast cancer
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Endometrial cancer
Follicular thyroid cancer
Multiple gastrointestinal (GI) hamartomas or ganglioneuromas
Macrocephaly (megalocephaly) (i.e., ≥97%, 58 cm in adult women, 60 cm in adult men)
Macular pigmentation of glans penis
Mucocutaneous lesions (e.g., one biopsy proven trichilemmoma, multiple palmoplantar keratosis, multifocal or
extensive oral mucosal papillomatosis, multiple cutaneous facial papules [often verrucous])
Minor criteria:
Autism spectrum disorder
Colon cancer
Esophageal glycogenic acanthosis (≥3)
Lipomas
Intellectual disability (i.e., IQ ≤75)
Papillary or follicular variant of papillary thyroid cancer
Thyroid structural lesions (e.g., adenoma, nodules, goiter)
Renal cell carcinoma
Single GI hamartoma or ganglioneuroma
Testicular lipomatosis
Vascular anomalies (including multiple intracranial developmental venous anomalies)
Available multi-gene screening panels that examine mutations in genes associated with breast and ovarian
cancer include, but are not limited to:
•
•
•
™
BreastNext (Ambry Genetics, Aliso Viejo, CA): this is a next generation sequencing panel that
simultaneously analyzes 18 genes that may lead to increased risk for breast cancer. The test includes
testing of genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NBN,
NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11 and TP53.
BRCAplus (Ambry Genetics, Aliso Viejo, CA): this is a next-generation sequencing panel of six genes
associated with high risk for breast cancer (BRCA1, BRCA2, CDH1, PTEN, STK11, TP53)
BROCA (University of Washington, Seattle, WA): this is a panel that uses next-generation sequencing
to detect mutations in 40 genes that are associated with suspected hereditary cancer predisposition,
with a focus on syndromes that include breast or ovarian cancer. Testing can be ordered for a single
gene or subset of genes on the BROCA panel.
Panels have been developed that tests for mutations in genes associated with several different cancer
syndromes, including breast and ovarian cancer. Since these panels examine the genes associated with many
different syndromes, the clinical utility of these tests has not been established. Regarding multi-gene panels,
the NCCN notes that limitations include an unknown percentage of variants of unknown significance, uncertainty
of level of risk associated with most of the genes, and lack of clear guidelines on risk management of carriers of
some of these mutations. These tests include but are not limited to:
•
•
™
myRisk Hereditary Cancer (Myriad Genetics, Inc., Salt Lake City, UT): this test will examine genes
associated with eight cancer syndromes: breast, ovarian, colorectal, endometrial, melanoma,
pancreatic, gastric, and prostate. The genes include: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2,
EPCAM, APC, MUTYH Biallelic, MUTYH Monoallelic, CDKN2A (p16INK4a),CDKN2A (p14ARF),
CDK4,TP53, PTEN, STK11, CDH1, BMPR1A, SMAD4, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1,
RAD51C, and RAD51D.
™
CancerNext (Ambry Genetics, Aliso Viejo, CA): is a next generation sequencing panel that
simultaneously analyzes 28 genes associated with increased risk for breast, colon, ovarian, uterine and
other cancers. The genes on this panel include: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, BMPR1A,
CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1,
PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, SMAD4, STK11, and TP53.
Other Genetic Testing for Susceptibility to Breast Cancer
While the syndromes most strongly associated with breast cancers are BRCA1 or BRCA2 mutation syndromes,
there has been recent research in other genetic variants that may have a role in familial breast cancer. There is
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a suggestion that the remaining breast cancer susceptibility is polygenic in nature, meaning that a relatively
large number of low-penetrance genes are involved, with each locus expected to have a relatively small effect
on breast cancer risk and not produce dramatic familial aggregation or influence patient management (NCI,
2013a).
There are other research strategies that have been undertaken to identify low-penetrance polymorphisms
leading to breast cancer susceptibility. They include candidate gene and genome-wide searches. The candidate
gene approach involves selecting genes based on their known or presumed biological function, relevance to
carcinogenesis or organ physiology, and searching for or testing known genetic variants for an association with
cancer risk. This strategy relies on imperfect and incomplete biological knowledge, and has been relatively
disappointing (NCI, 2013a). Confirmed candidate breast cancer susceptibility genes include, but are not limited
to the following:
• CHEK2
• Ataxia telangiectasia (AT or ATM)
• BRIP1 (also known as BACH1)
• PALB2
• CASP8 and TGFB1
• RAD51C
The genome-wide association studies have largely replaced the candidate gene research. This involves a very
large number of single nucleotide polymorphisms (SNPs) (potentially 1,000,000 or more) that are chosen within
the genome and tested largely without regard to their possible biological function, but instead to capture more
uniformly all genetic variation throughout the genome. Genome-wide searches are demonstrating promise in
identifying common, low-penetrance susceptibility alleles for many complex diseases including breast cancer
(NCI, 2013a). However, further research is needed regarding the genetic and functional characterization. Until
their individual and collective influences on cancer risk are evaluated prospectively, they are not considered
clinically relevant (NCI, 2014a).
Examples of SNP testing include, but are not limited to:
®
• deCode BreastCancer test (deCode Diagnostic Laboratory, Reykjavik, Iceland): tests for genotypes for
seven known SNPs that have been linked to breast cancer.
™
• BREVAGen (Phenogen Sciences, Charlotte, NC): this test combines the individuals clinical risk
factors (Gail score) with seven specific genetic markers, or SNPs.
®
• OncoVue Breast Cancer Risk Test (InterGenetics® Oklahoma City, OK): this test examines 22 single
nucleotide polymorphisms (SNPs) in 19 genes.
Unlike guidelines and criteria that have been established for BRCA testing, criteria have yet to be defined for
requirements for when genetic testing of candidate genes or SNPs should be implemented in routine
diagnostics (Ripperger, et al., 2008). Specialty professional organizations, in their statements regarding breast
cancer susceptibility testing, have not included these methods of testing.
Management/Treatment Strategies for Patients with Known Mutations and At-Risk Relatives
Several strategies have been proposed for achieving the goal of reducing cancer risk for individuals with known
BRCA mutations. The NCCN guidelines include detailed strategies for at-risk patients (NCCN, 2014b). for
women this may include clinical breast exams (BSE), mammogram and breast magnetic resonance imaging
(MRI) screening, discussion of risk-reduction surgery and transvaginal ultrasound. For men this may include
BSE starting at age 35, mammogram and prostate cancer screening. For both men and women this may include
education regarding signs and symptoms of cancer(s), especially those associated with BRCA gene mutations,
and screening may be individualized based on cancers observed in the family.
Literature Review
Hilgart, et al. (2012) reported on an update to a Cochrane review (Sivell, et al., 2007). In the update, five new
trials were included, bringing the total number of included studies to eight. The included trials provided data on
1,973 participants and assessed the impact of cancer genetic risk assessment on outcomes including
perceived risk of inherited cancer, and psychological distress. Trials selected for inclusion included studies
looking at interventions for cancer genetic risk assessment delivery for familial breast cancer. Results of the
review suggests that cancer genetic risk-assessment services help to reduce distress, improve the accuracy of
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the perceived risk of breast cancer, and increase knowledge about breast cancer and genetics. The health
professional delivering the risk assessment does not appear to have a significant impact on these outcomes.
The authors concluded that the review found favorable outcomes for patients after risk assessment for familial
breast cancer; however, there were too few papers to make any significant conclusions about how best to
deliver cancer genetic risk-assessment services. The report identified further research needs to assess the best
means of delivering cancer risk assessment, by different health professionals, in different ways and in
alternative locations.
A systematic evidence review was performed to determine the impact of genomic tests that are used to guide
treatment for ovarian cancer on health outcomes in asymptomatic women (Myers, et al., 2006). The report was
issued by the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control and
Prevention’s (CDC) Division of Cancer Prevention and Control and the CDC’s National Office of Public Health
Genomics. In the near future, the EGAPP working group will be evaluating the evidence presented in the report
and making recommendations about the use of these tests for screening, diagnosis and treatment of ovarian
cancer. The review sought evidence regarding: the analytic performance of tests in clinical laboratories; the
sensitivity and specificity of tests in different patient populations; the clinical impact of testing in asymptomatic
women, women with suspected ovarian cancer, and women with diagnosed ovarian cancer; the harms of
genomic testing; and the impact of direct-to-consumer and direct-to-physician advertising on appropriate use of
tests. The reviewers constructed a computer simulation model to test the impact of different assumptions about
the natural history of ovarian cancer on the relative effectiveness of different strategies. The review noted that
genomic test sensitivity/specificity estimates are limited by small sample size, spectrum bias, and unrealistically
large prevalence of ovarian cancer. The reviewers found no evidence relevant to the question of the impact of
these tests on health outcomes in asymptomatic women. It was noted in the review that there was no evidence
found that genomic tests for ovarian cancer have unique harms beyond those common to other tests for genetic
susceptibility or other tests used in screening, diagnosis, and management of ovarian cancer. The reviewers
noted that limitations of the review were that there was no attempt to perform meta-analysis of specific tests due
to the heterogeneity in design and patient populations; and many of the key parameters used in modeling
ovarian cancer incidence and mortality are unknown and, in some cases, unknowable. The authors concluded
that, although the research remains promising, adaptation of genomic tests into clinical practice must await
appropriately designed and powered studies in relevant clinical settings.
Professional Societies/Organizations
American College of Obstetricians and Gynecologists (ACOG): ACOG published clinical management
guidelines regarding hereditary breast and ovarian cancer syndrome. Included in the guidelines are criteria for
genetic risk assessment, which include the following (ACOG, 2009/2011):
• Patients with greater than an approximate 20–25% chance of having an inherited predisposition to
breast cancer and ovarian cancer and for whom genetic risk assessment is recommended:
1
 women with a personal history of both breast cancer and ovarian cancer
1
2
 women with ovarian cancer and a close relative with ovarian cancer or premenopausal breast
cancer or both
1
 women with ovarian cancer who are of Ashkenazi Jewish ancestry
2
1
 women with breast cancer at age 50 years or younger and a close relative with ovarian cancer
or male breast cancer at any age
 women of Ashkenazi Jewish ancestry in whom breast cancer was diagnosed at age 40 years or
younger
2
 women with a close relative with a known BRCA1 or BRCA2 mutation
• Patients with greater than an approximate 5–10% chance of having an inherited predisposition to breast
cancer and ovarian cancer and for whom genetic risk assessment may be helpful:
 women with breast cancer at age 40 years or younger
 women with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer of high grade,
serous histology at any age
 women with bilateral breast cancer (particularly if the first case of breast cancer was diagnosed
at age 50 years or younger)
2
 women with breast cancer at age 50 years or younger and a close relative with breast cancer
at age 50 years or younger
 women of Ashkenazi Jewish ancestry with breast cancer at age 50 years or younger
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
2
women with breast cancer at any age and two or more close relatives with breast cancer at any
age (particularly if at least one case of breast cancer was diagnosed at age 50 years or
younger)
2
 unaffected women with a close relative that meets one of the previous criteria
1
Cancer of the peritoneum and fallopian tubes should be considered a part of the spectrum of the hereditary
breast and ovarian cancer syndrome.
2
Close relative is defined as a first-degree relative (mother, sister, daughter) or second-degree relative
(grandmother, granddaughter, aunt, niece).
American Society of Clinical Oncology (ASCO): The ASCO published a policy statement regarding genetic
testing for cancer susceptibility. The ASCO statement includes recommendations that genetic counseling and
testing be offered when (ASCO, 2003; Robson, et al., 2010):
• The individual has personal or family history and the features suggestive of a genetic cancer
susceptibility condition.
• The genetic test can be adequately interpreted.
• The test results will aid in diagnosis or influence the medical or surgical management of the patient or
family members at hereditary risk of cancer.
In addition, the ASCO recommends that genetic testing only be done in the setting of pre- and post-test
counseling, which should include discussion of possible risks and benefits of cancer early detection and
prevention modalities. It is also noted by the ASCO that none of the cancer susceptibility tests currently
available is as yet appropriate for screening of asymptomatic individuals in the general population. However, in
the setting of clinically-defined cancer susceptibility syndromes or suggestive individual cancer histories with or
without family history information, the identification of a mutation in an affected member of the family may
influence medical management and can be used as a critical baseline in the testing of other family members
(ASCO, 2003; Robson, et al., 2010).
National Comprehensive Cancer Network (NCCN): The National Comprehensive Cancer Network
™
™
Guidelines (NCCN Guidelines ) include the following hereditary breast and/or ovarian cancer syndrome
testing criteria (NCCN, 2014b):
•
•
•
•
individual from a family with a known BRCA1/BRCA2 mutation
personal history of breast cancer (including invasive and ductal carcinoma in situ breast) plus one or
more of the following:
 diagnosed at age ≤45 years
 two breast primaries (including bilateral disease or cases where there are two or more clearly
separate ipsilateral primary tumors) when first breast cancer diagnosis occurred prior to age 50
 diagnosed at age ≤50 years with one or more close blood relative* with breast cancer at any
age
 diagnosed at age 50 or younger with a limited family history (e.g., fewer than two first- or
second degree female relatives or female relatives surviving beyond 45 years in either lineage)
 diagnosed at age 60 or younger with a triple negative breast cancer
 diagnosed at any age, with two or more close blood relatives* with breast cancer at any age
 diagnosed at any age with two or more close blood relatives* with pancreatic cancer at any age
 diagnosed at any age with two or more close blood relative with prostate cancer (Gleason score
≥7) at any age
 diagnosed at any age and there is at least one close blood relative* with breast cancer at age
50 or younger
 diagnosed at any age with one or more close blood relative with epithelial ovarian cancer,
4
fallopian tube, or primary peritoneal cancer
 close male blood relative with breast cancer
 for an individual of ethnicity associated with higher mutation frequency (e.g., Ashkenazi Jewish),
no additional family history may be required (testing for founder-specific mutation(s), if available,
should be performed first with full sequencing considered if other hereditary breast and/or
ovarian cancer criteria met)
personal history of epithelial ovarian (includes fallopian tube and primary peritoneal cancers) cancers
personal history of male breast cancer
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•
•
personal history of pancreatic cancer or prostate cancer (Gleason score ≥7) at any age with two or more
close blood relatives* with breast, and/or ovarian (includes fallopian tube and primary peritoneal
cancers) and/or pancreatic cancer or prostate cancer (Gleason score ≥7) at any age (for pancreatic
cancer, if Ashkenazi Jewish ancestry, only one additional relative is needed)
family history only with one of the following (Clinical judgment should be used to determine if the patient
has a reasonable likelihood of a mutation, considering the unaffected patient’s current age and the age
of female unaffected relative who link the patient with the affected relatives. Testing of unaffected
individuals should only be considered when an appropriate affected family member is unavailable for
testing. Significant limitations of interpreting test results for an unaffected individual should be
discussed):
 First- or second-degree blood relative that meets any of the above criteria
 Third-degree blood relative with breast and/or ovarian cancer (includes fallopian tube and
primary peritoneal cancers) cancer with two or more close blood relatives with breast cancer
(at least one with breast cancer ≤50 years) and/or ovarian cancer
*A close blood relative/close family member includes first-, second-, and third-degree relatives on the same side
of the family.
National Society of Genetic Counselors (NSGC): NSGC published practice guidelines for risk assessment
and genetic counseling for hereditary breast and ovarian cancer (Berliner, 2013). The guidelines include the
recommendations:
• Published guidelines should be consulted regarding the appropriateness of genetic testing, and a more
tailored approach to medical management should be addressed.
• Evaluation of families for hereditary breast and ovarian cancer (HBOC) syndrome should include
consideration of other hereditary syndromes in which breast and ovarian cancers are component
cancers.
• Standards of care for accurate risk assessment should be followed when identifying individuals at risk
for breast and/or ovarian cancers. Consider established models and published data to estimate the
individual’s risk of developing cancer, as this will assist in determining appropriate management as
summarized in the next recommendation.
• Clients should be given management recommendations based on clinical judgment, complemented by
risk assessment, family history and genetic test results (when appropriate).
• The genetics consultation should include the provision of extensive client resources including scientific
information, psychosocial support, and advocacy.
• Clients should be engaged in a discussion of the ethical, legal, and social implications of genetic
information and testing.
U.S. Preventive Services Task Force (USPSTF): The USPSTF published updated evidence-based
recommendations regarding the risk assessment, genetic counseling and genetic testing for BRCA-related
cancer in women (Moyer, et al., 2014). The recommendations include:
• The USPTF recommends primary care providers screen women who have family members with breast,
ovarian, tubal, or peritoneal cancer with one of several screening tools designed to identify a family
history that may be associated with an increased risk for potentially harmful mutations in breast cancer
susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should receive genetic
counseling and, if indicated after counseling, BRCA testing. (B recommendation)
• The USPSTF recommends against routine genetic counseling or BRCA testing for women whose family
history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or
BRCA2 genes. (D recommendation)
Use Outside of the US
National Institute for Health and Care Excellence (NICE) guidelines for familial breast cancer include the
following recommendations for genetic testing (NICE, 2013):
• Genetic testing:
 All eligible people should have access to information on genetic tests aimed at mutation finding.
 Pre-test counselling (preferably two sessions) should be undertaken.
 Discussion of genetic testing (predictive and mutation finding) should be undertaken by a healthcare
professional with appropriate training.
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
•
•
•
•
•
•
Eligible people and their affected relatives should be informed about the likely informativeness of
the test (the meaning of a positive and a negative test) and the likely timescale of being given the
results.
Mutation tests:
 Tests aimed at mutation finding should first be carried out on an affected family member where
possible.
 If possible, the development of a genetic test for a family should usually start with the testing of an
affected individual (mutation searching/screening) to try to identify a mutation in the appropriate
gene (such as BRCA1, BRCA2 or TP53)
 A search/screen for a mutation in a gene (such as BRCA1, BRCA2 or TP53) should aim for as close
to 100% sensitivity as possible for detecting coding alterations and the whole gene(s) should be
searched.
Carrier probability at which genetic testing should be offered:
 Discuss the potential risk and benefits of genetic testing. Include in the discussion the probability of
finding a mutation, the implications for the individual and the family, and the implications of either a
variant of uncertain significance or a null result (no mutation found).
 Inform families with no clear genetic diagnosis that they can request review in the specialist genetic
clinic at a future date.
 Clinical genetics laboratories should record gene variants of uncertain significance and known
pathogenic mutations in a searchable electronic database.
Genetic testing for a person with no personal history of breast cancer but with an available affected
relative:
 Offer genetic testing in specialist genetic clinics to a relative with a personal history of breast and/or
ovarian cancer if that relative has a combined BRCA1 and BRCA2 mutation carrier probability of
10% or more.
Genetic testing for a person with no personal history of breast cancer and no available affected relative
to test:
 Offer genetic testing in specialist genetic clinics to a person with no personal history of breast or
ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10% or more
and an affected relative is unavailable for testing.
Genetic testing for a person with breast or ovarian cancer:
 Offer genetic testing in specialist genetic clinics to a person with breast or ovarian cancer if their
combined BRCA1 and BRCA2 mutation carrier probability is 10% or more.
Genetic testing for BRCA1,BRCA2 and TP53 mutations within 4 weeks of diagnosis of breast cancer:
 Offer people eligible for referral to a specialist genetic clinic a choice of accessing genetic testing
during initial management or at any time thereafter.
 Offer fast-track genetic testing (within 4 weeks of a diagnosis of breast cancer) only as part of a
clinical trial.
 Discuss the individual needs of the person with the specialist genetics team as part of the
multidisciplinary approach to care.
 Offer detailed consultation with a clinical geneticist or genetics counsellor to all those with breast
cancer who are offered genetic testing, regardless of the timeframe for testing.
Summary
Genetic testing for cancer susceptibility provides patients and their physicians with information that will allow
them to make informed decisions regarding disease prevention, screening and surveillance, and treatment
options. There is a consensus in the medical literature that indicates BRCA testing is appropriate for a specific
subset of adult individuals who have been identified to be at high risk for hereditary breast and ovarian cancers.
Several specialty professional organizations have issued statements recognizing the role of BRCA testing in the
management of at-risk patients. In particular, the National Comprehensive Cancer Network (NCCN) publishes
clinical practice guidelines regarding assessment for hereditary breast and ovarian cancer that include specific
criteria for referral to risk assessment and counseling and consideration of genetic testing.
There is insufficient evidence in the published peer-reviewed medical literature to support the clinical utility of
candidate breast cancer susceptibility genes and single nucleotide polymorphisms [SNPs] testing for hereditary
breast and ovarian cancer syndrome. Impact of this testing on health outcomes has not been demonstrated.
Page 18 of 23
Coverage Policy Number: 0001
Specialty professional organizations that have issued statements regarding susceptibility to breast and ovarian
cancer testing have not recognized testing other than BRCA testing.
Coding/Billing Information
Note: 1) This list of codes may not be all-inclusive.
2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible
for reimbursement
Covered when medically necessary:
®
CPT *
Codes
81211
81212
81214
81215
81216
81217
Description
BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian
cancer) gene analysis; full sequence analysis and common duplication/deletion
variants in BRCA1 (ie, exon 13 del 3.835kb, exon 13 dup 6kb, exon 14-20 del
26kb, exon 22 del 510bp, exon 8-9 del 7.1kb)
BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian
cancer) gene analysis; 185delAG, 5385insC, 6174delT variants
BRCA1 (breast cancer 1) (eg, hereditary breast and ovarian cancer) gene
analysis; full sequence analysis and common duplication/deletion variants (ie,
exon 13 del 3.835kb, exon 13 dup 6kb, exon 14-20 del 26kb, exon 22 del 510bp,
exon 8-9 del 7.1kb)
BRCA1 (breast cancer 1) (eg, hereditary breast and ovarian cancer) gene
analysis; known familial variant
BRCA2 (breast cancer 2) (eg, hereditary breast and ovarian cancer) gene
analysis; full sequence analysis
BRCA2 (breast cancer 2) (eg, hereditary breast and ovarian cancer) gene
analysis; known familial variant
Covered when medically necessary when used to report uncommon large rearrangements/uncommon
®
duplication and deletion testing (e.g., BRACAnalysis Rearrangement Test [BART]):
®
CPT *
Codes
81213
Description
BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian
cancer) gene analysis; uncommon duplication/deletion variants
® ©
*Current Procedural Terminology (CPT ) 2013 American Medical Association: Chicago, IL.
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Page 23 of 23
Coverage Policy Number: 0001